Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

Active Project Grant Awarded Last action

Award ID
R01CA262112
Recipient
Awarding agency
Obligated
$5,146,005

Award facts

Assistance listing
93.393 Cancer Cause and Prevention Research
Completion date 94% complete
Place of performance
Memphis, TN 38103, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The lack of understanding how genetic variants affect molecular mechanisms that mediate tnbc aggression and impact effective anti-tumor therapies poses a substantial obstacle to advancement in cancer therapies. Current genetically engineered mouse models (gemms) of tnbc lack genetic complexity because mice are on a single inbred background which impairs the rigorous investigation into how individual genetic variation might impact tumor initiation, progression, or response to therapy. Because of this limitation, pre-clinical models typically fail to translate well to impact patient care. Although human studies have identified risk factors for developing tnbc with both environmental and genetics approaches, studies often fall short due to the inability to control variables or sample enough individuals. To address these limitations, we have pioneered a transformative approach with the creation of a novel murine model with robust, reliable, and reproducible phenotypic and genomic variation. We systematically crossed the C3(1)-tantigen (C3TAG) gemm, well established to resemble human basal-like tnbc, into the BXD family - the largest and best characterized genetic reference population. Preliminary data demonstrate that BXD-tnbc F1 isogenic hybrids have greatly differing severity of tnbc phenotypes, indicating genetic modifiers that impact disease. The advantage of the BXD-tnbc hybrids is that every genome is defined and reproducible. Using cutting edge systems genetics and molecular candidate validation, we will identify genetic modifiers of tnbc. Cross-species comparisons with publicly available human gwas and genomic databases will identify conserved, biologically relevant, and targetable candidates to yield highly impactful and readily translatable findings. We hypothesize that the interaction of modifier and causal genes govern the heterogeneity of tnbc phenotypes and alter response to therapy. Aim 1 will identify and validate novel genetic modifiers of tnbc phenotypes through unbiased systematic quantification of tnbc severity and heritability across BXD-tnbc hybrids. Pilot studies revealed candidate genes that impact patient survival in tnbc. Aim 2 will identify and validate novel genetic modifiers of therapeutic efficacy across BXD-tnbc hybrids. Last, the genetic contribution linking obesity and tnbc is currently unknown which is a problem because obesity exacerbates poor BC outcomes and reduces therapeutic efficacy in patients. Aim 3 will identify genetic modifiers of susceptibility to obesity exacerbated tnbc. Capitalizing upon our team's expertise, the overall objective is to interrogate this replicable genetic resource using established successful strategies to inform on the genetics of human risk and response to therapy. In SUM, the lack of targeted therapies for tnbc presents a great unmet clinical need. The deliverables of this novel BXD-tnbc will define susceptibility loci, candidate genes, and molecular networks that underlie variation of multiple tnbc phenotypes. Results generated will thus be transformative with high impact, leading to the identification of genes modifying heterogeneity and networks underlying individual differences in tnbc.

Transactions

Action Obligated Date
Amendment $41,106
Amendment $369,966
Amendment $369,966
Amendment $40,831
Amendment $40,831
Amendment $367,486
Amendment $367,486
Amendment $20,208
Amendment $20,208
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Amendment $363,752
Amendment $363,752
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Amendment $363,752
Amendment $404,735
Amendment $404,735
Amendment $404,735
Amendment $404,735
Original award $413,761
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Subawards

Subrecipient Amount Awarded
Duke University Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model $5,422

Quick answers

Who received award R01CA262112?

R01CA262112 was awarded to University Of Tennessee by National Cancer Institute (National Institutes of Health) on February 15, 2022.

How much is award R01CA262112 worth?

$5,146,005 has been obligated on R01CA262112.

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